6mol

From Proteopedia

(Difference between revisions)

Revision as of 11:02, 18 December 2019

Monoextended DARPin M_R12 complex with EpoR

Structural highlights

6mol is a 3 chain structure with sequence from Human and Synthetic construct sequences. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	EPOR (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EPOR_HUMAN] Defects in EPOR are the cause of familial erythrocytosis type 1 (ECYT1) [MIM:133100]. ECYT1 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin and hematocrit, hypersensitivity of erythroid progenitors to erythropoietin, erythropoietin low serum levels, and no increase in platelets nor leukocytes. It has a relatively benign course and does not progress to leukemia.^[1] ^[2] ^[3]

Function

[EPOR_HUMAN] Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase. Isoform EPOR-T acts as a dominant-negative receptor of EPOR-mediated signaling.

Publication Abstract from PubMed

Although tunable signaling by G protein-coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. This surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.

Topological control of cytokine receptor signaling induces differential effects in hematopoiesis.,Mohan K, Ueda G, Kim AR, Jude KM, Fallas JA, Guo Y, Hafer M, Miao Y, Saxton RA, Piehler J, Sankaran VG, Baker D, Garcia KC Science. 2019 May 24;364(6442). pii: 364/6442/eaav7532. doi:, 10.1126/science.aav7532. Epub 2019 May 23. PMID:31123111^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4495-9. PMID:8506290
↑ Sokol L, Prchal JF, D'Andrea A, Rado TA, Prchal JT. Mutation in the negative regulatory element of the erythropoietin receptor gene in a case of sporadic primary polycythemia. Exp Hematol. 1994 May;22(5):447-53. PMID:8174675
↑ Le Couedic JP, Mitjavila MT, Villeval JL, Feger F, Gobert S, Mayeux P, Casadevall N, Vainchenker W. Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies. Blood. 1996 Feb 15;87(4):1502-11. PMID:8608241
↑ Mohan K, Ueda G, Kim AR, Jude KM, Fallas JA, Guo Y, Hafer M, Miao Y, Saxton RA, Piehler J, Sankaran VG, Baker D, Garcia KC. Topological control of cytokine receptor signaling induces differential effects in hematopoiesis. Science. 2019 May 24;364(6442). pii: 364/6442/eaav7532. doi:, 10.1126/science.aav7532. Epub 2019 May 23. PMID:31123111 doi:http://dx.doi.org/10.1126/science.aav7532

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6mol"

@@ Line 3: / Line 3: @@
 <StructureSection load='6mol' size='340' side='right'caption='[[6mol]], [[Resolution|resolution]] 3.16&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mol]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mol]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOL FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPOR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mol FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mol OCA], [http://pdbe.org/6mol PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mol RCSB], [http://www.ebi.ac.uk/pdbsum/6mol PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mol ProSAT]</span></td></tr>
 </table>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 6mol" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Erythropoietin receptor|Erythropoietin receptor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
+[[Category: Synthetic construct sequences]]
 [[Category: Garcia, K C]]
 [[Category: Guo, Y]]

6mol

From Proteopedia

Revision as of 11:02, 18 December 2019

Monoextended DARPin M_R12 complex with EpoR

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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